Malaria parasites have developed widespread resistance to standard antimalarial drugs, such as chloroquine. Olliaro, P. L.; Boland, P. B. Clinical Public Health Implications of Antimalarial Drug Resistance. In Antimalarial Chemotherapy: Mechanisms of Action, Resistance, and New Directions in Drug Discovery; Rosenthal, P. J., Ed.; Humana Press: Totowa, N.J., 2001; pp. 65-83. Therefore, use of non-alkaloidal 1,2,4-trioxanes, such as artemisinin (qinghaosu 1, FIG. 1), combined with a standard alkaloidal antimalarial drug, is now recommended by the World Health Organization (WHO); Guidelines for the Treatment of Malaria; World Health Organization: Geneva, 2006.
This type of artemisinin combination therapy (ACT) features very rapid clearance of parasites by the trioxane, as well as prolonged antimalarial activity by an alkaloid, each with a different mechanism of action. Ashley, E. A.; White, N. J. Artemisinin-based Combinations. Curr. Opin. Infect. Dis. 2005, 18, 531-536; Adjuik, M., et al., Artesunate Combinations for Treatment of Malaria: Meta-analysis. Lancet 2004, 363, 9-17; Guthmann, J.-P., et al., High Efficacy of Two Artemisinin-based Combinations (Artesunate plus Amodiaquine and Artemether plus Lumefantrine) in Caala, Central Angola. Am. J. Trop. Med. Hyg. 2006, 75, 143-145; Myint, H. Y., et al., Efficacy and Safety of Dihydroartemisinin-piperaquine. Trans. R. Soc. Trop. Med. Hyg. 2007, 101, 858-866; Sirima, S. B., et al., The Efficacy and Safety of a New Fixed-dose Combination of Amodiaquine and Artesunate in Young African Children with Acute Uncomplicated Plasmodium falciparum. Malar. J. 2009, 8, 48; de Pilla Varotti, F., et al., Synthesis, Antimalarial Activity, and Intracellular Targets of MEFAS, a New Hybrid Compound Derived from Mefloquine and Artesunate. Antimicrob. Agents Chemother. 2008, 52, 3868-3874.
One current ACT drug features a three-day, six-dose adult regimen totaling approximately 480 mg of artemether (2b, FIG. 1) and 2,880 mg of the amino-alcohol lumefantrine. Sagara, I., et al., A Randomized Trial of Artesunate-mefloquine versus Artemether-lumefantrine for Treatment of Uncomplicated Plasmodium falciparum Malaria in Mali. Am. J. Trop. Med. Hyg. 2008, 79, 655-661. Another current ACT drug features a three-day, three-dose adult regimen totaling approximately 600 mg of sodium artesunate (2c, FIG. 1) and 750 mg of the quinoline antimalarial mefloquine. Bhatt, K. M., et al., Efficacy and Safety of an Artesunate/mefloquine Combination, (Artequin) in the Treatment of Uncomplicated P. falciparum Malaria in Kenya. East Afr. Med. J. 2006, 83, 236-242. Patient compliance with adhering to a repeated dose regimen, however, is often problematic. A recent study reports a two-day treatment of dihydroartemisinin-piperaquine phosphate-trimethoprim, which reported better patient compliance than the artemether-lumefantrine combination. Menan, H., et al., Comparative Study of the Efficacy and Tolerability of Dihydroartemisinin-Piperaquine-Trimethoprim versus Artemether-Lumefantrine in the Treatment of Uncomplicated Plasmodium falciparum Malaria in Cameroon, Ivory Coast and Senegal, Malar. J. 2011, 10, 185-193. Nevertheless, a single dose oral cure is highly desirable. A recent report features a single dose oral cure of P. berghei malaria-infected mice using synthetic 1,2,4-trioxolane ozonide OZ439 (3, FIG. 1). Charman, S. A., et al., Synthetic Ozonide Drug Candidate OZ439 Offers New Hope for a Single-dose Cure of Uncomplicated Malaria. PNAS, 2011, 108, 4400-4405.
Single-dose oral cures of P. berghei-infected mice have been reported previously using trioxane dimer sulfone carbamate 5 (FIG. 1), Rosenthal, A. S., et al., Malaria-infected Mice are Cured by a Single Oral Dose of New Dimeric Trioxane Sulfones Which are Also Selectively and Powerfully Cytotoxic to Cancer Cells. J. Med. Chem. 2009, 52, 1198-1203, using a dimer orthoester sulfone 6 (FIG. 1), Moon, D. K., et al., A Single, Low, Oral Dose of a 5-Carbon-linked Trioxane Dimer Orthoester Plus Mefloquine Cures Malaria-infected Mice. Bioorg. Med. Chem. Lett. 2011, 21, 2773-2775, and using trioxane monomer 4-fluoroanilide (12a). Woodard, L. E., et al., Malaria-Infected Mice Live Until at Least Day 30 After a New Monomeric Trioxane Combined with Mefloquine are Administered Together in a Single Low Oral Dose. J. Med. Chem. 2009, 52, 7458-7462. New single-dose, oral cures for malaria, however, remain of interest.